The present invention relates to 5,11-dihydrodiaryl[b,e][1,4]oxazepine derivatives, antagonistic to calcium channels and useful for treating or preventing functional diseases of gastrointestinal tracts, in particular, irritable bowel syndrome, and stereoisomers thereof, pharmacologically acceptable salts thereof or hydrates thereof and also pharmaceutical compositions containing any of them as the active ingredient.
The present invention also relates to intermediates for producing the new 5,11-dihydrodiaryl[b,e][1,4]oxazepine derivatives.
It is disclosed in, for example, European Patent No. 0404359 that the 5,11-dihydrodibenzo[b,e][1,4]thiazepine derivatives are useful as antagonists to calcium channels, which are selective for the gastrointestinal tracts. Quinn, P. et al. [Brit. H. Pharmacol., 1994, 112 (Suppl.), Abst. P. 573] and Wallis, R. M. et al. [Brit. J. Pharmacol., 1994, 112 (Suppl.), Abst. P. 574]disclosed that (S)-5-[[1-(4-methoxyphenyl)ethyl]pyrrolidin-2-ylmethyl]-5,11-dihydrodibenzo[b,e]-[1,4]thiazepine maleate has the same effect as the one described above. However, the activity and selectivity of those compounds for the gastrointestinal tracts are not yet satisfactory and another defect of them is that they have an anticholinergic effect that causes side effects such as a thirst and mydriasis. Further, International Patent Nos. 9733885A1 and 9912925A1 disclose 5-(2-pyrrodinylmethyl)-5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives as agents for improving the movement of the digestive tracts. In addition, International Patent No. 0040570A1 discloses 5-alkyl-5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives as agents for improving the movement of the digestive tracts. However, the activity and selectivity of those compounds for the gastrointestinal tracts is not yet satisfactory and they have not yet been used as drugs.
As the social environment is being complicated recently, many people are under great stress and patients suffering from irritable bowel syndrome and having abnormal bowel movement and abdominal pain as the cardinal symptoms are increasing in number. Drugs used for ameliorating such diseases are, for example, a cholinergic blocking drug, laxatives, antidiarrheal drug, drug for intestinal disorders, mucosal paralyzant, agent for regulating gastrointestinal motor functions, agent for regulating autonomic nerves, herb medicine, antianxiety drug, antidepressant drug, sleeping pill, antipsychotic drug, serotonin receptor antagonist and serotonin receptor agonist. However, the clinical effects of those drugs are yet insufficient and they are not always satisfactory because of the side effects. Under these circumstances, the development of a new type of drugs having an excellent effect of improving functional gastrointestinal diseases and free of side effects is desired.